Hantavirus Cardio-Pulmonary Syndrome (HCPS) due to Sin Nombre Virus has a mortality rate of 45% while HCPS due to Andes virus is at least as severe, with death due to cardiogenic shock and non-cardiogenic pulmonary edema. Current evidence indicates that the pathology of HCPS/SNV is mediated at least in part by an exuberant T cell-mediated immune response against HSV-infected endothelial cells. This notion is supported by recent evidence that patients with severe or fatal HCPS express a specific class I MHC allele, HLA-B*35. Since the GB35- restricted nucleocapsid protein epitope is conserved between SNV and Andes viruses, the same association between HCPS severity and B*35 allele may occur among hospitalized patients with HCPS in Chile. This proposal test the hypothesis that severe hantavirus disease (shock and pulmonary edema is directly related to one or more MHC alleles through their role regulating the intensity of the cytotoxic T cell response. One hundred fifty hospitalized patients with HCPS will be HLA-typed at class I (A, B and C loci) and class II will be compared. This study will also test the hypothesis that the intensity of cytokine gene transcription and subsequent organ damage is determined in lesser part by allelic polymorphisms in HLA-linked genes, particularly in the TNF complex linked to HLA-B loci. Finally, in contrast to susceptibility to severe disease, susceptibility to infection with Andes virus is not associated with allelic polymorphisms in the MHC complex, as tested in a field study of seropositive versus seronegative individuals. Detailed analysis will seek to identify individual contributions of one or multiple MHC alleles determining disease severity. Planned parallel studies in North and South America on the immunogenetics of hantavirus infection will enhance the insights from each syndrome. The strategy of 'reverse immunogenetics" of hantavirus infection will enhance the insights from each syndrome. The strategy of 'reverse immunogenetics' may identify specific cellular or cytokine targets for future therapeutic interventions.